Method and apparatus for determining the left-ventricular ejection time TLVE of a heart of a subject

ABSTRACT

In order to reliably determine the left-ventricular ejection time T LVE  of a heart of a subject, at least two different measuring methods are employed. This includes in any case the derivation of a first waveform related to thoracic electrical bioimpedance or bioadmittance. A second waveform can be determined by using pulse oximetry, Doppler velocimetry, measurement of arterial blood pressure and measurement of peripheral electrical bioimpedance or bioadmittance. Depending on signal quality, the results obtained by each method are weighted and then averaged. The weighted average for left-ventricular ejection time is used as an input variable for cardiovascular monitoring methods, which determine objective measurements of cardiovascular function and performance. Such measurements include, but are not limited to, left ventricular ejection fraction, stroke volume, cardiac output, systolic time ratio, and indices of ventricular contractility.

[0001] This application claims the benefit of U.S. provisionalapplication No. 60/328,694, filed Oct. 11, 2001, of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a method and an apparatus fordetermining the left-ventricular ejection time T_(LVE) of a heart of asubject.

[0004] T_(LVE) is the temporal interval defining the mechanical periodfor ejection of blood from the left ventricle of a subject's heart.T_(LVE) temporally refers to the ejection phase of mechanical systole.T_(LVE) commences with opening of the aortic valve, and ends with aorticvalve closure. The accurate measurement of T_(LVE) is of paramountimportance in the calculation of left ventricular stroke volume, cardiacoutput, and systolic time ratio.

[0005] Stroke volume (SV), and specifically left ventricular SV, is thequantity of blood ejected from the left ventricle into the aorta overT_(LVE), or the ejection phase of mechanical systole, over one cardiaccycle, or heart beat. Cardiac output (CO) is the quantity of bloodejected from the left ventricle per minute, i.e., depends on SV andheart rate (HR). HR is the number of heartbeats per minute. CO is theproduct of SV and HR, i.e.,

CO=SV·HR.

[0006] Accurate, serial, quasi, or non-static determinations of SV, andthus, CO, are rigidly dependent on the accurate measurement of T_(LVE).

[0007] 2. Description of the Related Art

[0008] In the related art, T_(LVE) was derived from curves obtained bymeasurements of a thoracic electrical bioimpedance or bioadmittance(TEB). In young, healthy individuals, the measurement of TEB results inwaveforms that routinely exhibit, and readily permit, identification ofthe opening of the aortic valve (point “B”) and its closure (point “X”)by visual inspection. However, in various states and degrees ofcardiopulmonary pathology, point “X” is commonly obscured or absent, seeLababidi Z, Ehmke D A, Durnin R E, Leaverton P E, Lauer R M.: The firstderivative thoracic impedance cardiogram. Circulation 1970; 41: 651-658.These are, unfortunately, the situations where accurate T_(LVE)measurements are mandatory.

[0009] In a further advanced method, simultaneous electronicregistration of the first time-derivative of the cardiac-relatedimpedance change waveform generated by TEB, and the mechanicallygenerated heart sounds obtained via phonocardiography, were employed fordetermination of T_(LVE), and specifically, aortic valve closure (firsthigh frequency registration of the second heart sound). Unfortunately,the technique of phonocardiography is cumbersome, sensitive to motionand ventilation artifacts (low signal-to-noise ratio), and is unsuitedfor routine clinical application.

[0010] To the present time, alternative methodology is limited tofrequency spectrum domain analysis (Wang et al., U.S. Pat. No.5,443,073; 5,423,326; 5,309,917) and to the establishment of temporal“expectation windows” for predictive estimation of periodic landmarkoccurrences, namely, aortic valve closure, and the duration between suchlandmarks, namely, T_(LVE).

[0011] Regarding the latter method, Weissler et al. (Weissler A M,Harris W S, Schoenfeld C D. Systolic time intervals in heart failure inman. Circulation 1968; 37: 149-159, incorporated herein by reference)empirically determined, with heart rate as the variable, regressionequations for the temporal interval defining and predictingelectromechanical systole (known as “QS₂”) and the subordinate timeintervals contained within, comprising, in particular, the leftventricular flow, or ejection time T_(LVE). Bleicher et al. (Bleicher W,Kemter B E, Koenig C. Automatische kontinuierliche Vermessung desImpedanzkardiogramms. Chapter 2.6 In: Lang E, Kessel R, Weikl A [eds.].Impedanz-Kardiographie. Verlag C M Silinsky, Nürnberg, Paris, London1978) compares the regression equations reported by Weissler with thoseof other investigators (Spitaels S. The influence of heart rate and ageon the systolic and diastolic time intervals in children. Circulation1974; 49: 1107-1115. Kubicek W G. The Minnesota impedance cardiograph.Theory and applications. Biomed Engineering September 1974.) Weisslerremains the “gold standard” within the statistical-based methods. Withtemporal reference to the electrocardiogram and the predeterminedtemporal occurrence of aortic valve opening obtained by an alternativemethod, these regression equations predict time intervals which can thenbe used to estimate the magnitude of T_(LVE) and, thus, the temporaloccurrence of aortic valve closure. A time-predictive expectation windowcan be bracketed around a predicted occurrence of aortic valve closureto confirm the point of measured aortic valve closure assessed by analternative method.

[0012] However, the application of an expectation window, employed asthe only alternative method for determining T_(LVE), is based on errorprone, statistical methods. While correlation (the closeness ofassociation) between the regression equations and measured values ofT_(LVE) is clinically acceptable, time-predictive expectation windowsinherently possess unacceptably large standard deviations due toindividual biologic variability. In contradistinction, inherentlyaccurate, alternative, objective measurements of T_(LVE) are limited inaccuracy solely by the precision of the measurement device, which ispresupposed to have a much smaller error of the estimate. Thus,time-predictive expectation windows have only limited validity within asingle, discreet cardiac cycle. Moreover, the predictive accuracyfurther deteriorates in the presence of cardiac rhythms, which are notof regular sinus origin. In the presence of irregularly, irregularchaotic rhythms of supraventricular origin, such as atrial fibrillationwith variable ventricular response, or other irregular supraventriculartachydysrhythmias, the use of time-predictive expectation windows arerendered virtually all but useless. In the presence of sinus orpathologic supraventricular rhythms, coexisting with electrical systolesgenerated from ventricular origins, known as premature ventricularcontractions, accurate assessment of mean values for T_(LVE) based ontime-predictive expectation windows is impossible.

SUMMARY OF THE INVENTION

[0013] It is an object of the present invention to provide a method andan apparatus for determining the left-ventricular ejection time T_(LVE)of a heart of a subject more reliably, in particular in those situationsin which the determination of T_(LVE) with the related art methods isinsufficient, namely in some states of cardiopulmonary pathology.

[0014] According to the invention, the measurement of the thoracicelectrical bioimpedance or thoracic electrical bioadmittance (TEB) isused for deriving a waveform from which the left-ventricular ejectiontime can be determined. However, in addition to that method, at least asecond waveform is derived. For the derivation of this second waveform,the present invention offers a variety of different methods. Thesemethods include, but are not limited to

[0015] a) the continuous extrapolation of arterial blood oxygensaturation (SpO₂) values by means of pulse oximetry,

[0016] b) the use of Doppler velocimetry, in particular

[0017] b₁) the use of Doppler velocimetry applied to the esophagus,and/or

[0018] b₂) the use of Doppler velocimetry applied to the radial artery,

[0019] c) the measurement of arterial blood pressure, in particular

[0020] c₁) the continuous invasive measurement of arterial bloodpressure, and/or

[0021] c₂) the continuous noninvasive measurement of arterial bloodpressure (applanation tonometry, or sphygmocardiography).

[0022] Each of these methods can provide continuous waveforms withcharacteristic patterns related to either an arterial pressure or flowpulse wave.

[0023] Each method, when applied, determines T_(LVE), beat-by-beat.Ideally, a signal processor receives the continuous waveforms providedby each method in parallel, performs synchronization in time, and thendetermines a “method averaged”, or “final”, T_(LVE). The contribution ofeach method applied depends on the level of acceptable signal quality.In the preferred embodiment, each method's contribution to the “methodaveraged” T_(LVE) is weighted, based on the level of acceptable signalquality. The weights can be fixed, i.e., predetermined, or also can beadapted depending on signal quality parameters, such as the noise level.

[0024] Alternatively, the “method-averaged” T_(LVE) is determined byidentifying “common” points in time for opening and closure of theaortic valve, which requires that all waveforms are exactly alignedsynchronously with time.

[0025] In order to further improve the inventive method, an expectationwindow for T_(LVE) can be established by using a regression equation,prior to precisely determining T_(LVE). The latter improvement is inparticular useful in those cases wherein the determination of aorticvalve closure from the waveform is ambiguous.

[0026] In order to make use of the inventive method, the inventionprovides a system suited to perform some of the various methodsmentioned above but need not apply to each method. In a preferredversion of the invention, the system is suited to perform threedifferent of the above-mentioned methods, i.e., the thoracic electricalbioimpedance/bioadmittance measurement (TEB) and two additional methods.

[0027] The apparatus according to the invention can be tailor-made forthe respective application in which the apparatus is to be used. In manycases, a combination of an apparatus for obtaining a thoracic electricalbioimpedance/bioadmittance (TEB) waveform and a pulse oximeter issufficient.

[0028] For an anesthesiologist, a combination of a TEB apparatus and aDoppler velocimeter is preferred. In this case, the thoracic electricalbioimpedance or bioadmittance is measured by electrodes placed on acatheter, or probe, which is adapted to be inserted into the esophagus.An ultrasound crystal being part of a Doppler velocimeter also isincorporated into the catheter, or probe. The trunk of a patient underanesthesia is often covered with sterile blankets. The patient's headremains the only part of the upper body being easily accessible. Hence,the practical approach to obtain waveforms from which T_(LVE) can bederived is inserting a catheter, or probe, into the patient's esophagus.The apparatus tailored for the anesthesiological applications can, as athird unit, also includes a pulse oximeter having a probe attached to apatient's finger or toe, because, in a lot of cases, the hand or thefoot of the patient subject also is readily accessible.

[0029] For a doctor investigating the vasculature, for example, in ahypertension clinic, an apparatus including a bioimpedance analyzer, apulse oximeter and other methods accessing the “peripheral” bloodpressure is ideally suited. In this context, a peripheral method isdefined as method which can be applied to an extremity (limb) of apatient. Peripheral methods include Doppler velocimetry applied to theradial artery, and the invasive measurement of arterial blood pressure,wherein a sensor is inserted into an artery of an extremity of apatient. Alternatively, applanation tonometry or sphygmocardiography canbe used.

[0030] The inventive system is not limited to the above examples. Inparticular, other combinations are imaginable, as long as TEB is used.Furthermore, a system is part of the invention which includes any of theabove-mentioned methods or devices, such that the system can be used ina variety of different fields and applications.

[0031] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

[0032] The accompanying drawings, which are incorporated in andconstitute a part of this specification, illustrate several embodimentsof the invention and together with the description, serve to explain theprinciples of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033]FIG. 1 schematically shows a system/apparatus according to oneembodiment of the present invention, and its electrical interfaces witha subject.

[0034]FIG. 2 schematically shows an alternative system/apparatusaccording to another embodiment of the present invention.

[0035]FIG. 3 illustrates the processing of waveform data obtained byvarious methods for determining a method-averaged T_(LVE) of increasedaccuracy.

[0036]FIG. 4 illustrates parallel recordings of a surfaceelectrocardiogram (ECG), the change in thoracic bioimpedance, ΔZ(t)(“Delta Z”), and the rate of change of bioimpedance, dZ(t)/dt.

[0037]FIG. 5 illustrates parallel recordings of a surfaceelectrocardiogram (ECG), the change in thoracic bioadmittance, ΔY(t)(“Delta Y”), and the rate of change of bioadmittance, dY(t)/dt.

[0038]FIG. 6 illustrates light absorbance in living tissue.

[0039]FIG. 7 illustrates a pulse plethysmogram obtained by pulseoximetry.

[0040]FIG. 8 illustrates how a catheter comprising electrodes for a TEBmeasurement and a Doppler velocimeter is placed in the human esophagusfor the measurement of the left-ventricular ejection time, theleft-ventricular stroke volume, and the cardiac output.

[0041]FIG. 9a shows a raw signal obtained from esophageal Dopplervelocimetry during mechanical systole.

[0042]FIG. 9b shows the signal of FIG. 9a after smoothing (filtering).It graphically demonstrates the method how TLVE is extracted from theDoppler velocity waveform.

[0043]FIG. 10 shows a curve obtained by a Doppler velocimeter transducerplaced over the radial artery.

[0044]FIG. 11 demonstrates that the morphology of a velocity-versus-timewave derived from radial artery applanation tonometry is akin to aninvasively derived pressure waveform.

[0045]FIG. 12 demonstrates waveform tracings derived from the ECG,oximeter derived pulse plethysmogram, and invasive radial arterial bloodpressure, respectively.

[0046]FIG. 13a illustrates the method by which a time domain isconstructed for predicting the temporal occurrence of aortic valveclosure.

[0047]FIG. 13b illustrates the Q-S₂ interval at a heart rate of 60 bpm,shown within a cardiac cycle of the ECG and corresponding rate of changeof impedance waveform.

[0048]FIG. 13c illustrates the Q-S₂ interval at a heart rate of 100 bpm,shown within a cardiac cycle of the ECG and corresponding rate of changeof impedance waveform.

[0049]FIG. 13d illustrates the Q-S₂ interval at a heart rate of 140 bpm,shown within a cardiac cycle of the ECG and corresponding rate of changeof impedance waveform.

[0050]FIG. 14a illustrates the method by which an expectation window isestablished for predicting the T_(LVE).

[0051]FIG. 14b illustrates T_(LVE) at a heart rate of 60 bpm, shownwithin a cardiac cycle of the ECG and corresponding rate of change ofimpedance waveform.

[0052]FIG. 14c illustrates T_(LVE) at a heart rate of 100 bpm, shownwithin a cardiac cycle of the ECG and corresponding rate of change ofimpedance waveform.

[0053]FIG. 14d illustrates T_(LVE) at a heart rate of 140 bpm, shownwithin a cardiac cycle of the ECG and corresponding rate of change ofimpedance waveform.

DETAILED DESCRIPTION OF THE DRAWINGS

[0054] Reference will now be made in detail to the present preferredembodiments (exemplary embodiments) of the invention, an examples ofwhich are illustrated in the accompanying drawings. Wherever possible,the same reference numbers will be used throughout the drawings to referto the same or like parts.

[0055]FIG. 1 schematically shows a system according to the presentinvention, and its electrical interfaces with a subject 10. A dashedline indicates the subject's areas of interest to which an apparatusaccording to this invention can be applied.

[0056] The measurement of thoracic electrical bioimpedance (orbioadmittance), which is part of all embodiments of the presentinvention, is performed by one of the two different methods: In thefirst, more commonly used method, surface electrode arrays 14 areapplied to the thorax of the subject. For example, tetrapolar arrays ofspot electrodes are placed on each side of the neck and on each side ofthe lower part of the thorax, at the level of the xiphoid process.Alternatively, electrodes are located on an esophageal catheter, orprobe 16, and this catheter, or probe 16, is inserted into the esophagus18. Either surface electrode arrays, or the electrodes for theesophageal catheter, or probe, are connected to an electricalbioimpedance (or bioadmittance) analyzer 20. The preferred apparatus formeasurement of bioimpedance, or bioadmittance, and the correspondingelectrode montage of electrode arrays, are described and shown in U.S.patent application Ser. No. 09/824,942 [Bernstein/Osypka] incorporatedherein by reference. The bioimpedance, or bioadmittance, measuringapparatus 20 applies a low amplitude, high frequency alternating current(AC) through the outer electrodes, measures a corresponding voltage dropbetween the inner electrodes, and calculates the bioimpedance, orbioadmittance. Hence, if the bioimpedance is determined, the measuredvoltage magnitude is divided by the applied current sent through theelectrodes, and electrical bioimpedance analyzer 20 processes acontinuous impedance signal

Z(t)=Z ₀ +ΔZ(t),

[0057] comprising of a quasi-constant offset, Z₀, or base impedance, anda pulsatile component, ΔZ(t), related to the cardiac cycle.

[0058] In this context, “continuous” presupposes that this waveformcontains a stream of discrete, digital samples, and, thus, is notlimited to a truly continuous, analog waveform.

[0059] The continuous ΔZ waveform, which can be considered as an imageof an aortic blood flow signal superimposed on an aortic volume changesignal, is transferred to a processing unit 22, along with thesimultaneously obtained value for the base impedance Z₀.

[0060] By the apparatuses mentioned above, a first waveform can bederived from which a first value for the left-ventricular ejection timeT_(LVE) can be determined.

[0061] The system according to the invention offers a vast variety ofpossibilities for deriving at least one second waveform from whichT_(LVE) can also be determined.

[0062] A first one of these possibilities relates to determining theblood flow velocity in the aorta. To this end, an esophagealcatheter/probe, with an ultrasound crystal sensor 24 incorporated at thetip, is placed into the subject's esophagus 18. In the event that theelectrodes for the bioimpedance measurements are placed on acatheter/probe, the same catheter can be used both for the bioimpedancemeasurement and for Doppler velocimetry. Ultrasound crystal sensor 24 isconnected to a Doppler velocimeter 26. Doppler velocimeter 26 transfersa continuous voltage, corresponding to aortic velocity, to processingunit 22.

[0063] Another possibility for deriving a second curve is pulseoximetry. The subject's area of interest is here a finger or toe 28 (theperipheral vasculature). For obtaining signals, an infrared emitter 30as well an infrared sensor 32 are applied to the fingertip or toe. Thedata obtained by sensor 32 re sent to a pulse oximeter 34. The lattertransfers an oxygen saturation waveform (which is continuously obtained)to processing unit 22.

[0064] Another apparatus also measures the electrical bioimpedance.However, it is not the bioimpedance across the thorax of the subject.Rather, an impedance signal obtained at the limbs 36 (the peripheralvasculature) of the subject is used to measure a second waveform fromwhich T_(LVE) can be derived. To this end, an array of four surfaceelectrodes 38 are applied to an arm or a leg of the subject. As in thecase of the measurement of the thoracic electrical bioimpedance, analternating current (AC) source applies a low amplitude, high frequencycurrent through the outer electrodes, and a voltage drop is measured bya voltmeter between the inner electrodes. Alternatively, an array of twosurface electrodes is utilized, using each electrode for currentapplication and voltage sensing. The data are processed in an electricalbioimpedance analyzer 40 which is also connected to processing unit 22.

[0065] Three further methods that may be incorporated into theapparatuses of certain embodiments of the present invention are directedtowards the peripheral vasculature of the arm or the wrist 42. The firstof the apparatuses performs Doppler velocimetry by attaching anultrasound transducer 44 to the radial artery at the wrist. Dataobtained by the transducer are transferred to a Doppler velocimeter 46,and the data are further processed in processing unit 22, which isconnected to Doppler velocimeter 46.

[0066] Another apparatus is based on the indirect measurement of theblood pressure in the radial artery. A pressure sensor 48, or an arrayof pressure sensors, is attached to the subject's wrist 42, over theradial artery, and is connected to an applanation tonometer 50. Theapplanation tonometer transfers a continuous voltage, corresponding toperipheral arterial blood pressure, to processing unit 22.

[0067] The blood pressure can also be measured invasively by placing apressure sensor 52 mounted on a catheter in the radial artery. The datafrom the pressure sensor are transferred to a unit 54 which is connectedto processing unit 22.

[0068] The processing unit determines, from each continuous waveformobtained, the temporal occurrence of aortic opening (point “B”) andclosure (point “X”). The possible range of temporal occurrences ofaortic valve closure is limited by time predictive expectation windows,established around points approximated by heart-rate dependentregression equations, such as proposed by Weissler mentioned above.Potential “X” points, closer to the predicted X point, are weighteddifferently than those farther away.

[0069] When applicable, each method contributes to a “final”,method-averaged T_(LVE), which is used for the calculation of strokevolume and other cardiodynamic parameters relying on T_(LVE). Dependingon subject 10 under measurement, and his/her state of health, thevarious methods will not necessarily perform with the same degree ofaccuracy and reliability. The ability of a method to determine aorticvalve opening and, especially, aortic valve closure, depends on thesignal quality of the waveforms obtained. Thus, the preferred embodimentweights the T_(LVE) contributions corresponding to each signal quality.

[0070] The “final” T_(LVE) is displayed on a display and control panel56 which at the same time serves for controlling the whole system.

[0071] In the preferred embodiment, the different units for processingthe data, i.e., electrical bioimpedance analyzer 20 and 40, Dopplervelocimeters 26 and 46, pulse oximeter 34, and applanation tonometer 50are incorporated into a single device together with processing unit 22and display and control panel 56. This single device is indicated at 58and represented by a dashed line. Electrical bioimpedance analyzers 20and 40 may be of similar design, and Doppler velocimeters 26 and 46 maybe of similar design, too, or used alternatively for the esophageal orradial artery approach. Only those parts of the systems which areapplied to subject 10 can, of course, not be implemented in device 58.However, the device 58 is provided with interfaces for each of themeasuring devices 14, 16, 24, 30/32, 38, 44, 48, and 52/54.

[0072] Whilst in FIG. 1, an embodiment is shown in which all possibleunits are part of a single device 58, FIG. 2 schematically shows howT_(LVE) can be obtained by using various methods and merged into a mostreliable, “final” T_(LVE) determination. In particular, FIG. 2 shows asystem of different apparatuses which need not necessarily beincorporated into a single device.

[0073] The system comprises a trans-thoracic or esophageal bioimpedanceapparatus 60. In the context of this application, and in particular alsoin the claims, “thoracic electrical bioimpedance”, or TEB, is notlimited to the transthoracic approach using surface electrodes, butincludes the application of measuring electrical bioimpedance orbioadmittance within the esophagus. Therefore, apparatus 60 is shown asa single apparatus 60 which can be considered as a first apparatus formeasuring thoracic electrical bioimpedance. Bioimpedance apparatus 60can be replaced by a bioadmittance apparatus. The TEB apparatus 60transfers an impedance signal to a signal processor 62. At the sametime, an electrocardiogram (ECG) can be obtained by apparatus 60 whichis also transferred to signal processor 62. Signal processor 62processes these data and determines a part of Z₀ of the impedance signalwhich does not change during one heart stroke, the time-derivation dZ/dtand in particular the minimum dZ/dt_(MIN) of the derivation, theleft-ventricular ejection time T_(LVE) and the period T_(RR), i.e., thetime between two peaks in the ECG. All these data are transferred to amain processing unit 64.

[0074] TEB apparatus 60 is needed in all embodiments of systemsaccording to the invention.

[0075] The system according to the invention includes at least onesecond apparatus selected from the group of apparatuses described in thefollowing.

[0076] A first of these additional apparatuses is an esophageal Dopplervelocimeter 66 which transfers a velocity signal to a signal processor68 which derives a value of T_(LVE) from the velocity signal andtransfers this value to main processing unit 64.

[0077] Alternatively, or in addition, a radial artery Dopplervelocimeter 70 can be used which transfers a velocity signal to a signalprocessor 72 which derives a value of T_(LVE) from the velocity signaland transfers this value to main processing unit 64.

[0078] Furthermore, a pulse oximeter 74 can be provided which transfersa plethysmogram to a signal processor 76. The signal processor 76derives a value of T_(LVE) from the plethysmogram and transfers thisvalue to main processing unit 64.

[0079] Moreover, a peripheral electrical bioimpedance 78 can be used toderive an impedance signal which is transferred to a signal processor80, which determines a value of T_(LVE) from said impedance signal andtransfers it to main processing unit 64.

[0080] Another possibility is the use of an applanation tonometer 82sending a blood pressure signal to a signal processor 84. Signalprocessor 84 determines a value of T_(LVE) from said blood pressuresignal and transfers it to main processing unit 64.

[0081] Instead of an applanation tonometer, or in addition thereto, aninvasive arterial blood pressure measurement apparatus 86 can be usedwhich transfers a blood pressure signal to a signal processor 88, thelatter also deriving a value of T_(LVE) from the blood pressure signal.Main processing unit 64 determines the “method-averaged”, or “final”T_(LVE), based on the T_(LVE) measurements of the various availablemethods, and their signal quality. The T_(LVE) measurement provided by amethod with questionable signal quality will be considered with lessstatistical weighting than the T_(LVE) measurement provided by a methodwith acceptable signal quality. For each method, a preferably adaptivetime-predictive, expectation window may or may not be applied.

[0082] The “final” T_(LVE) is used to determine the stroke volume.According to a preferred embodiment, the stroke volume is calculated byusing the following formula:${{SV} = {V_{EFF} \cdot \sqrt{\frac{( \frac{{Z(t)}}{t} )_{MIN}}{Z_{0}}} \cdot \frac{T_{LVE}}{\sqrt{T_{RR}}}}},$

[0083] wherein V_(EFF) is the effective volume of electricalparticipating thoracic tissue. When V_(EFF) is given in milliliters, thestroke volume SV is also obtained in milliliters. This formula has beenpresented for the first time in the application Ser. No. 09/824,942(Bernstein/Osypka) mentioned and incorporated above. The cardiac outputis the stroke volume, multiplied with the heart rate.

[0084] The values finally obtained by main processing unit 64 are outputto a display and control panel 90.

[0085]FIG. 3 illustrates the processing of waveform data obtained byvarious methods for determining a method-averaged T_(LVE) of increasedaccuracy for computation of stroke volume and other cardiodynamicparameters relying on T_(LVE).

[0086] The “final”, method-averaged T_(LVE) can be obtained by, but isnot limited to, transferring the results of the various T_(LVE)measurements through decision-node logic or a neural network. U.S. Pat.No. 6,186,955 describes a method employing a neural network to optimizedetermination of cardiac output. In a similar manner, waveform datarecorded by a method measuring blood flow or blood pressure, or acombination thereof, such as thoracic electrical bioimpedance (TEB) 92,or bioadmittance, pulse oximetry (POX) 94, Doppler velocimetry (EDV 96and RDV 98), applanation tonometry (ATN) 100, peripheral electricalbioimpedance (PEB) 102, or bioadmittance, or invasively measuredarterial blood pressure (ABP) 104, are used as inputs to a neuralnetwork determining a “final”, method-averaged T_(LVE) of increasedaccuracy. In this implementation, a processing unit 106 determines theweighting factors based on the applicability and use of a method, andempirically derived criteria for signal quality (SQI=signal qualityindicator). The operator can influence the decision process by enablingor disabling the method contributions, and thus the weighting, through adisplay and control panel 108.

[0087] In the following, the different methods for obtaining values ofT_(LVE) are described in detail, one after another.

[0088] The determination of T_(LVE) from thoracic bioimpedance orbioadmittance is a standard method in the determination of the strokevolume (see the application of Bernstein and Osypka mentioned andincorporated by reference above).

[0089]FIG. 4 illustrates the parallel recordings of a surfaceelectrocardiogram (ECG), the change in thoracic bioimpedance, ΔZ(t)(“Delta Z”), and its first time-derivative, $\frac{{Z(t)}}{t}.$

[0090] In the ECG, point “Q” is defined as the onset of ventriculardepolarization, i.e., beginning of electrical systole.

[0091] Points “B” and “X” are characteristic points on the firsttime-derivative $\frac{{Z(t)}}{t}:$

[0092] Point “B” is indicated by a significant change in slope of thedZ(t)/dt waveform immediately preceding a strong decrease of dZ(t)/dt.This change in slope is often observed as a notch prior to the strongdecrease of dZ(t)/dt up to its minimum, $\frac{{Z(t)}}{t_{MIN}}.$

[0093] Point “B” occurs approximately 55-65 milliseconds prior to$\frac{{Z(t)}}{t_{MIN}}$

[0094] and can be readily determined by using well-known methods ofwaveform analysis using a microprocessor or computer.

[0095] Point “X” is the next maximum in the dZ(t)/dt waveform following$\frac{{Z(t)}}{t_{MIN}}$

[0096] and can be readily determined by using well-known methods ofwaveform analysis using a microprocessor or computer.

[0097] Point “B” is defined as the opening of aortic valve and marks thebeginning of the ejection phase of left-ventricular systole.

[0098] Point “X” is defined as the closure of aortic valve and marks theend of the ejection phase of left-ventricular systole.

[0099] Accordingly, the left-ventricular ejection time is defined as thetime interval between point “B” and point “X”.

[0100] Point “Y” is defined as the closure of the pulmonic valve, i.e.,point “Y” marks the endpoint of right-ventricular systole. In a subjectwith anatomically normal intracardiac electrical conduction pathways(without presence of a left bundle branch block), point “Y” followspoint “X” in time. The “O” wave in the $\frac{{Z(t)}}{t}$

[0101] waveform corresponds to rapid ventricular filling in earlydiastole. The time interval between point “Q” and point “B” is known asthe pre-ejection period (T_(PE)).

[0102]FIG. 5 illustrates the parallel recordings of a surfaceelectrocardiogram (ECG), the change in thoracic admittance, ΔY(t)(“Delta Y”), and its first time-derivative, $\frac{{Y(t)}}{t}.$

[0103] Points “Q”, “B”, “X” and “O” are equivalent to FIG. 4, and,consequently, T_(LVE) and T_(PE).

[0104] With respect to pulse oximetry, FIG. 6 illustrates lightabsorbance in living tissue. The baseline, static component (analog toDC) represents absorbance of the tissue bed, venous blood, capillaryblood, and non-pulsatile arterial blood. The pulsatile component (analogto AC) is due solely to pulsatile arterial blood.

[0105] In pulse oximetry, light is sent through living tissue (targettissue), and the light absorbance in that tissue is detected. Pulseoximeters utilize two wavelengths of light, one in the red band, usually660 nm, and one in the infrared band, usually 940 nm. Light emittingdiodes in the signal probe located at one side of the target tissue(usually the finger) emit light of the appropriate wavelength. Theintensity of the light transmitted through the tissue is measured by aphoto-detector located on the opposite side. Transmitted lightintensities of each wavelength are sampled hundreds of times per pulsecycle. The variation in absorption of light that is sensed as the bloodvessels expand and contract with each arterial pressure pulse isregistered.

[0106] As arterial blood pulses in the fingertip, the path length oflight increases slightly. This increase in path length and lightabsorption is due solely to the augmented quantity of hemoglobin inarterial blood. Hence, pulse oximetry is a non-invasive method fordetermining the saturation of red blood cell hemoglobin with oxygen.Since this saturation is directly related to the heart stroke, thetemporal interval between opening and closure of aortic valve, T_(LVE),can be derived from a plethysmogram obtained by pulse oximetry.

[0107] In pulse oximetry, it is assumed that the only pulsatileabsorbance between the light source and photo detector is the arterialblood. The oximeter first determines the AC component of the absorbanceat each wavelength and then divides this AC component by thecorresponding DC component to derive “pulse added” absorbance hat isindependent of the incident light intensity. It then calculates theratio$R = {\frac{\frac{{AC}_{660}}{{DC}_{660}}}{\frac{{AC}_{940}}{{DC}_{940}}}.}$

[0108] The pulsatile waveform of the AC component takes the shape of anattenuated arterial pressure pulse tracing.

[0109]FIG. 7 shows three waveforms, wherein the waveform shown at thebottom is a pulse plethysmogram obtained by pulse oximetry, and whereinthe two other curves are electrocardiograms shown for comparison. Ofthat waveform, two points T₁ and T₂ are indicated. T₁ is the foot of astrong upslope and corresponds to a local minimum in the plethysmogramwhich can be readily determined by using well-known methods of waveformanalysis using microprocessors or computers. T₂ is the dicrotic notchequivalent on the deceleration phase of the signal. T₂ can be readilydetermined by searching for an abrupt change in the derivative of theplethysmogram by using well-known waveform analysis methods.

[0110] The time interval between T₁ and T ₂ corresponds to the timeinterval between points “B” and “X” on the bioimpedance waveform. Thus,it is precisely equivalent to the temporal interval between opening andclosure of aortic valve (T_(LVE)), except for a transit time delay ofthe propagated arterial pressure/flow pulse wave measured from proximalto distal sampling site. The time delay (ΔT) is dependent on thedistance between aortic root and pulse oximetry sampling location, andon the ‘stiffness” of the arterial system. ΔT, however, has no effect onT_(LVE).

[0111] While prior art utilizes the method of pulse oximetry determiningthe saturation of red blood cell hemoglobin with oxygen, aplethysmogram, as shown in FIG. 7, is used for other purposes thandisplay. Commonly, a microprocessor or computer analysis determines themaximal oxygen saturation level and the heart rate. The determination ofT_(LVE) from a plethysmogram obtained by pulse oximetry, however, is notknown in prior art.

[0112] An alternative or additional method to obtain a value of T_(LVE)is Doppler velocimetry. Doppler velocimetry makes use of the Dopplerprinciple. According to the Doppler principle, the frequency of wavesemitted by a moving object is dependent on the velocity of that object.In Doppler velocimetry, an ultrasonic wave of constant magnitude (in theMHz range) is emitted into the axial direction of an artery comprisingred blood cells which correspond to the above-mentioned moving object.The ultrasonic wave is reflected by the red blood cells (back-scattered)and the reflected wave is detected. Depending on the velocity of the redblood cells, the frequency of the reflected ultrasound is altered. Thedifference in frequency between the ultrasound emitted (f₀) and thatreceived (f_(R)) by the Doppler transducer produces a frequency shift

Δf=f _(R) −f ₀.

[0113] This instantaneous frequency shift depends upon the magnitude ofthe instantaneous velocity of the reflected targets, their directionwith respect to the Doppler transducer, and the cosine of the angle atwhich the emitted ultrasound intersects with the targets. Theinstantaneous frequency shift (Δf_(i)) is, like velocity, a vector,since it possesses the characteristics of both magnitude and direction.Instantaneous red blood cell velocity (v₁) and the corresponding Dopplerfrequency shift (Δf_(i)) are related by the Doppler equation, which isgiven as:${{\Delta \quad f_{i}} = {\frac{{2 \cdot f_{0} \cdot \cos}\quad \theta}{c} \cdot _{i}}},$

[0114] where Δf_(i) is the instantaneous frequency shift (measured inKHz),

[0115] f₀ is the emitted, constant magnitude ultrasonic frequency(measured in MHz),

[0116] c is the speed (propagation velocity) of ultrasound in tissue(blood), usually in the range of 1540-1570 m/s,

[0117] θ is the incident angle formed by the axial flow of red bloodcells and the emitted ultrasonic signal, and wherein

[0118] v_(i) is the instantaneous red blood cell velocity within thescope of the interrogating ultrasonic perimeter or target volume.

[0119] By algebraic rearrangement:$v_{i} = {\frac{c}{2 \cdot f_{0}} \cdot {\frac{\Delta \quad f_{i}}{\cos \quad \theta}.}}$

[0120] Since c and f₀ are constants,$v_{i} = {k \cdot {\frac{\Delta \quad f_{i}}{\cos \quad \theta}.}}$

[0121] Moreover, if θ=0°, then cos θ=1, and then

v ₁ =k·Δf ₁,

[0122] and

v _(i) ≈Δf _(i).

[0123] The system according to the preferred embodiment makes use of twodifferent kinds of Doppler velocimeters.

[0124] In one example, a Doppler velocimeter is placed in the humanesophagus. FIG. 8 illustrates how this method is performed: A Dopplertransducer 110 is affixed to the tip of a pliable plastic catheter 112having a diameter of about 6 mm. That catheter 112 is inserted into theesophagus 114 of a subject (patient) 116. When properly aligned, theDoppler transducer senses the peak ultrasound Doppler frequency shift,proportional to peak aortic blood velocity, as well as the entiretime-velocity sequence of ventricular ejection. Since the descendingaorta 118 is located in close proximity to esophagus 114, Dopplertransducer 110 can emit ultrasound which is reflected by blood in theaorta (indicated by the series of curves near transducer 110 in FIG. 8).

[0125] If the frequency shift Δf_(i) is measured, the aortic blood flowvelocity can be derived according to the formula discussed above. FIG.9a shows a signal obtained by esophageal Doppler velocimetry. FIG. 9bshows the signal of FIG. 9a after smoothing. T_(LVE) can be determinedby defining the point T₁ when the aortic blood flow velocity starts toexceed the value of zero, and by defining the point T₂ when the aorticblood flow velocity again reaches a value of zero in the smoothed curve.The esophageal Doppler velocimetry is ideally suited for measurement ofT_(LVE) because of the close proximity of sensor 110 to descending aorta118.

[0126] If the aortic valve cross-sectional area (CSA) is known, eitherby echocardiographic measurement, or by nomogram, integration of thetime-velocity signal produces SV when the integral of velocity and CSAare multiplied. SV can be calculated as the product of CSA and thesystolic velocity integral, known as SVI, obtained at the site ofmaximum flow amplitude.

[0127] According to an alternative Doppler velocimetry method, a Dopplervelocimeter transducer is placed over the radial artery. This method isknown in the prior art and is used in order to obtain information aboutthe total blood flow through the radial artery. However, usually nowaveforms are derived from such a measurement.

[0128] However, such a waveform can readily be derived. FIG. 10illustrates such a waveform representing the velocity of flowing bloodversus time. One can define a first point T₁ corresponding to a localminimum in the waveform preceding an upslope ending at the total maximumin a period of the curve. This local minimum can readily be determinedby using well-known computer-analysis systems.

[0129] Furthermore, a second point T₂ can be determined which is theabsolute minimum of a period of the curve following a part of the curvedescending from the maximum. This point can be determined by computeranalysis, too.

[0130] The time interval between T₁ and T₂ corresponds to the timeinterval between points “B” and “X” on the impedance or admittancewaveforms. Thus, it is precisely equivalent to the temporal intervalbetween opening and closure of aortic valve (T_(LVE)), except for atransit time delay of the propagated arterial pressure/flow pulse wavemeasured from proximal to distal sampling site.

[0131] The pulsatile changes in the periphery follow the pulsatilechanges in the aorta by a time delay (ΔT), which is dependent on thedistance between aortic root and sampling location on the radial arteryat the wrist, and on the ‘stiffness” the arterial system. ΔT, however,has no effect on T_(LVE).

[0132] According to an alternative, or additional, method of determiningT_(LVE), the arterial blood pressure is measured. Non-invasive orinvasive methods can be used therefore.

[0133] Arterial tonometry (a special form of sphygmocardiography) is atechnique employed to measure arterial blood pressure noninvasively. Atonometric instrument provides a continuous measurement of bloodpressure, as well as registering the sensed waveform. Its continuousnature is thus akin to direct, invasive blood pressure methods. Like itsinvasive counterpart, arterial tonometry is usually applied to theradial artery. Tonometric measurements require a superficial arteryclose to an underlying bone. The radial artery is most commonly usedbecause it is easily accessible, closely apposed to bone, and thetransducer can be easily stabilized at the wrist.

[0134] Applanation tonometry typically involves a transducer, includingone or more pressure sensors positioned over a superficial artery. Theradial artery at the wrist is a preferred superficial artery. Manual ormechanical hands-off affixation methods provide steady pressureapplication to the transducer, so as to flatten (applanate) the wall ofthe underlying artery without occluding it. The pressure measured by thesensor is dependent upon the applied affixation pressure used totransfix the transducer against the skin of the patient, and on thearterial blood pressure transducer component, which is ideally alignedperpendicular to the axial flow of arterial blood.

[0135] Tonometric systems measure a reference pressure directly from thewrist and correlate this with arterial pressure. The tonometer sensorcontinuously transduces the arterial pressure pulse from systolicexpansion and deceleration to aortic valve closure, and throughdiastolic decay and recoil. The radial arterial waveform signal isregistered.

[0136]FIG. 11 illustrates a waveform derived from radial arteryapplanation tonometry, i.e., a representation of the measured bloodpressure versus time. In FIG. 11, the first point T₁ is defined where aminimum of the waveform occurs, followed by a steep upslope of thesignal. This minimum can be readily determined by using computeranalysis. The minimum is followed by an upslope to a maximum, andafterwards the curve is descending again and reaches a first minimum inwhich the point T₂ is defined. Such a minimum can readily be determinedby using computer methods for waveform analysis. The time intervalbetween T₁ and T₂ corresponds to the time interval between points “B”and “X” on the admittance waveform. Thus, it is precisely equivalent tothe temporal interval between opening and closure of aortic valve(T_(LVE)), except for a transit time delay of the propagated arterialpressure/flow pulse wave measured from proximal to distal sampling site.

[0137] The pressure changes in the periphery follow the pressure changesin the aorta by a delay (ΔT), which is dependent on the distance betweenaortic root and tonometric sampling location and on the ‘stiffness” ofthe arterial system. ΔT, however, has no effect on T_(LVE).

[0138] The measurement of the radial arterial blood pressure can also bedetermined invasively. An invasive arterial pressure tracing isextracted by cannulation of the radial artery. A transducer connected bya fluid column provides a continuous pressure waveform that is used todetermine the approximate arterial pressure. It is assumed that properzeroing and calibration of the transducer has been effected.

[0139] When the clinical situation dictates the need for accurate,continuous blood pressure measurement, as well as frequent bloodsampling for arterial blood gas analysis, cannulation of the femoral,brachial, and especially the radial artery is common.

[0140]FIG. 12 illustrates a tracing obtained by invasive radial arterialblood pressure (curve on the bottom). For comparison, anoximeter-derived pulse plethysmogram (in the middle) and anelectrocardiogram (ECG) are also shown. In a similar manner as in thecase of FIG. 11, in the blood pressure tracing of FIG. 12, a first pointT_(1ALN) is defined as a local minimum of the waveform, preceding bysteep increase of the pressure waveform. A second point T_(2ALN) isdefined as significant change in slope following the absolute maximum ofthe plethysmogram. Both points can be readily determined by usingcomputer waveform analysis. Also shown are the two points T_(1POX) andT_(2POX), which have been determined in the same manner as describedabove with respect to FIG. 7.

[0141] It is to be noted that the time interval on the oximeter tracingT_(1POX) to T_(2POX) is equivalent to the time interval derived from theinvasive pressure tracing, T_(1ALN) to T_(2ALN). Both modalities, thenoninvasive and the invasive approaches, respectively, describe the sameapproximation of T_(LVE), albeit with a temporal delay from its aorticorigins.

[0142] Invasively derived blood pressure is one of the most reliablemethods for the determination of T_(LVE), despite that this fact is notcommonly acknowledged in the prior art. The derivation of T_(LVE) bymeans of invasively derived blood pressure can be used as a standard bywhich all the preceding methods are assessed.

[0143] The continuous waveforms obtained from thoracic electricalbioimpedance, or bioadmittance, esophageal Doppler velocimetry, radialartery Doppler velocimetry, pulse oximetry, applanation tonometry andinvasive arterial cannulation, demonstrate, regardless of disease state,a distinct slope change upon opening of aortic valve, or equivalentupstroke of peripheral propagated pressure/flow pulse waves. However,timing of aortic valve closure, especially by waveform analysis of TEB,is sometimes obscured by the severity of the disease state, which mayrender this temporal landmark electronically indecipherable. Therefore,the critical determinant of T_(LVE) is usually the timing of aorticvalve closure. Therefore, to circumvent this problem, temporalexpectation windows can be constructed by two methods: either byapproximating the timely occurrence of the closure of aortic valve aspredicted, or by the width of T_(LVE) itself, as predicted. TABLE 1Regression equations for the QS₂ interval after Weissler et al. GenderRegression equation; [QS₂] in s Standard Deviation Male QS₂ = −0.0021 ·HR + 0.546 0.014 s Female QS₂ = −0.0020 · HR + 0.549 0.014 s

[0144]FIGS. 13a-d illustrate the method by which a time domain isconstructed for predicting the temporal occurrence of aortic valveclosure. Weissler et al. (see article cited above) establishedregression equations for the duration of the systolic time intervalsbased on recordings of the electrocardiogram, phonocardiogram, andcarotid arterial pulse tracing. Regarding the time domain expectationwindow for closure of the aortic valve, the predictive regressionequation for the duration of the QS₂ interval is employed (Table 1).Point “Q” is defined as the onset of ventricular depolarization, i.e.,beginning of electrical systole. Point “Q” can be readily determined asthe local minimum in the electrocardiogram preceding the main peak inthe electrocardiogram. Point ‘S₂” is defined by phonocardiography as thesecond heart sound and corresponds to aortic valve closure. Anexpectation window can be constructed by establishing temporal limitsprior to and after the predicted point in time. Depending upon thetimely occurrence of measured aortic valve closure, by any of theaforementioned methods, within or outside the expectation windows, analgorithmically determined nominal point of aortic valve closure isassigned. The inherent error of this approach is determined by theconfidence intervals of the estimate. An alternative method for theconstruction of an expectation window is to establish weighted means ofall timely occurrences of indicated closure points depending on thetemporal distance from the predicted closure of the aortic valve.

[0145] This technique can be applied to any of the invasive andnoninvasive methods described above. The closure of the aortic valve(the end of T_(LVE)) corresponds to the ejection phase of systole, orthe end of the Q-S₂ time interval (electromechanical systole),determined by phonocardiography. Weissler et al. determined that Q-S₂ isindependent of the disease state and virtually constant at any heartrate HR, while T_(LVE) is highly variable. Therefore, the expectationwindow for T_(LVE) is focused on the expected occurrence of the end ofQS₂. The regression equations for QS₂, as shown in Table 1, are notapplicable or valid in the presence of iatrogenically inducedintraventricular conduction delay of the left bundle branch block type(i.e., single chamber ventricular pacing) or in pathologically occurringleft bundle branch block.

[0146]FIGS. 14a-d illustrate the method an expectation window isestablished for T_(LVE). Weissler et al. (see article cited above)determined the regression equations (Table 2) for systolic timeintervals in normal individuals. These regression equations are notapplicable for all patients categorized by certain cardiopulmonaryabnormalities. TABLE 2 Regression equations for T_(LVE) after Weissleret al. Gender Regression equation; [T_(LVE)] in s Standard DeviationMale T_(LVE) = −0.0017 · HR + 0.413 0.010 s Female T_(LVE) = −0.0016 ·HR + 0.418 0.010 s

[0147] The user of the invention can implement one, a combination, orall, alternative aforementioned methods delineated, dictated by theclinical situation, the constraints of time, and the necessity for nearabsolute accuracy of stroke volume, cardiac output and systolic timeratio measurements determined by means of TEB.

[0148] Since T_(LVE) is linearly and highly correlated negatively withheart rate (HR), time domains related to standard regression equationsmay be used to identify the time domain in which aortic valve closure isstatistically expected to occur. Algorithmic decision nodes, based onstatic requirements and/or artificial neural networks, can determinewhich method, or methods, provides the most accurate assessment ofT_(LVE).

[0149] In each of the methods described above, the expectation windowfor the closure of aortic valve (see FIGS. 13a-d) or for the width ofT_(LVE) itself (see FIGS. 14a-d) can be useful, and those criteria usedto define the points in the respective curve which are employed todetermine T_(LVE). By the application of the expectation windows, errorsin the determination of these respective points can be considerablyreduced.

[0150] If the closure of aortic valve (point “X”) can be definitively bedetermined by signal analysis in conjunction with time windows, thisinterval will be entered into computation.

[0151] If signal failure occurs, such that no alternative method canprovide accurate T_(LVE) measurements, the invention will default tostandard regression equations, and/or alert the user of inappropriatesignal quality. In the rare case that the alternative methods fail toprovide precise T_(LVE) measurements, the invention can default toT_(LVE) determined by means of TEB.

[0152] Though the system according to the invention has been describedto include apparatuses for employing a plurality of alternative methods,those systems will fall under the scope of the invention in which theTEB apparatus for determining T_(LVE) is combined with at least a secondapparatus. Preferably three out of the alternative methods discussedabove are implemented in a system according to the invention. Thespecific system used may be dependent upon the specific purpose forwhich the system is to be used, in particular for the special field inwhich the medical specialists using the system works.

[0153] Other embodiments of the invention will be apparent to thoseskilled in the art from consideration of the specification and practiceof the invention disclosed herein. It is intended that the specificationand examples be considered as exemplary only, with a true scope andspirit of the invention being indicated by the following claims.

I claim:
 1. A method of determining the left-ventricular ejection timeT_(LVE) of a heart of a subject, comprising: deriving a first waveformincluding measuring a value selected from the group comprising thoracicelectrical bioimpedance and thoracic electrical bioadmittance over time;deriving at least a second waveform by using a method selected from thegroup comprising pulse oximetry, Doppler velocimetry, measurement ofarterial blood pressure, measurement of peripheral electricalbioimpedance, and measurement of peripheral electrical bioadmittance;and using said first waveform and at least said second waveform in orderto determine T_(LVE).
 2. The method according to claim 1, wherein saidsecond waveform is derived by using pulse oximetry.
 3. The methodaccording to claim 1, wherein said second waveform is derived by usingpulse oximetry, and wherein said pulse oximetry measures the intensityof light absorbed by a finger of the subject, wherein light is emittedat one side of the finger and light is detected at the other side of thefinger.
 4. The method according to claim 3, wherein two wavelengths oflight are utilized in pulse oximetry, the first wavelength being in thered band and the second wavelength being in the infrared band.
 5. Themethod according to claim 1, wherein said second waveform is derived byusing Doppler velocimetry.
 6. The method according to claim 1, whereinsaid second waveform is derived by using esophageal Doppler velocimetry.7. The method according to claim 5, wherein a Doppler velocimeter isapplied to a radial artery of the subject.
 8. The method according toclaim 1, wherein said second waveform is derived by using pulseoximetry, and wherein a third waveform is derived by using esophagealDoppler velocimetry, and wherein said first, second, and third waveformsare used to determine T_(LVE).
 9. The method according to claim 6 or 8,wherein the deriving of said first waveform comprises placing at leasttwo electrodes on a catheter and inserting said catheter into theesophagus of the subject, and wherein the esophageal Doppler velocimetryis performed by using a transducer placed on said same catheter.
 10. Themethod according to claim 1, wherein said second waveform is derived byusing pulse oximetry, and wherein a third waveform is derived by usingone of the group comprising Doppler velocimetry at a radial artery ofthe subject, non-invasive measurement of blood pressure in a radialartery of the subject, and wherein said first, second, and thirdwaveforms are used to determine T_(LVE).
 11. The method according toclaim 1, wherein at least a third waveform is derived by using a methoddifferent from the method used to derive said first and secondwaveforms, and wherein said first, second, and third waveforms are usedto determine T_(LVE).
 12. The method according to claim 1 or 11,wherein: a) in a first step, all of said waveforms are independentlyused to determine T_(LVE) by applying predetermined criteria to definethe opening point and the closure point of the aortic valve in saidwaveforms, and wherein b) in a second step, the values of T_(LVE)obtained are averaged by using predetermined weights for the T_(LVE)values obtained from all of said waveforms.
 13. The method according toclaim 1 or 11, wherein: a) predetermined criteria are used toindependently define the opening point and the closure point of theaortic valves in all of said waveforms, b) all of said waveforms arealigned synchronously with time, c) the opening points defined in saidwaveforms are used to derive an averaged opening point by usingpredetermined criteria, d) the closure points defined in said waveformsare used to derive an averaged closure point by using predeterminedcriteria, and wherein e) T_(LVE) is determined by calculating the timeinterval starting with said averaged opening point and ending at saidaveraged closure point.
 14. The method according to claim 1, wherein anexpectation window for T_(LVE) is established prior to preciselydetermining T_(LVE).
 15. The method according to claim 14, wherein saidexpectation window is established on the basis of a regression equationfor T_(LVE) in dependence on the heart rate HR.
 16. A system fordetermining the left-ventricular ejection time T_(LVE) of a heart of asubject, comprising: a first apparatus for measuring a value selectedfrom the group comprising thoracic electrical bioimpedance and thoracicelectrical bioadmittance over time; and at least one second apparatusselected from the group comprising: an apparatus for derivingplethysmogram data, an apparatus for deriving signal data representingthe velocity of blood in an artery in the vicinity of the esophagus ofthe subject, an apparatus for deriving signal data representing thevelocity of blood in radial artery of the subject, a first apparatus formeasuring data representing the blood pressure in an artery of thesubject, said first apparatus for measuring data comprising a pressuresensor adapted to be non-invasively attached to the subject, a secondapparatus for measuring data representing the blood pressure in anartery of the subject, said second apparatus for measuring datacomprising a pressure sensor adapted to be inserted into an artery ofthe subject, an apparatus for measuring peripheral electricalbioimpedance, and an apparatus for measuring peripheral electricalbioadmittance.
 17. The system according to claim 16, further comprising:a device coupled to said first apparatus for determining a value ofT_(LVE) from the values measured by said first apparatus, for each ofsaid second apparatus selected from the group: a device coupled to therespective second apparatus for determining a value of T_(LVE) from thedata obtained by said apparatus, and a device for averaging alldetermined values of T_(LVE) according to p redetermined weights. 18.The system according to claim 16, further comprising: a device coupledto said first apparatus for defining the opening and the closure time ofthe aortic valve of the subject on the basis of the values measured bysaid first apparatus, and for each of said second apparatus selectedfrom the group: a device coupled to the respective second apparatus fordetermining the opening and the closure time of the aortic valve of thesubject on the basis of the data obtained by said second apparatus, adevice for deriving an averaged opening time of the aortic valve on thebasis of all opening times defined by respective devices, a device forderiving an averaged closure time of the aortic valve on the basis ofall closure times defined by respective devices, a device forcalculating a time from said averaged opening time to said averageclosure time.
 19. The system according to claim 16, further comprisingat least one of the devices selected from the group of a display fordisplaying the value of T_(LVE) determined by said system, an outputline for electronically outputting the value of T_(LVE) determined bysaid system, and a printer for printing out the value of T_(LVE)determined by said system.
 20. The system according to claim 16, whereinsaid first apparatus comprises: at least two electrodes; an alternatingcurrent (AC) source; a voltmeter; and a processing unit for calculatingsaid value.
 21. The system according to claim 20, wherein saidelectrodes are adapted to attach to the thorax of the subject.
 22. Thesystem according to claim 20, wherein said electrodes are placed on acatheter adapted to be inserted in the esophagus of the subject.
 23. Thesystem according to claim 20, wherein said second apparatus is anapparatus for deriving signal data representing the velocity of blood inan artery in the vicinity of the esophagus of the subject, said secondapparatus comprising a transducer attached to a catheter, and whereinsaid at least two electrodes of said first apparatus are also placed onsaid catheter.
 24. A system for determining the left-ventricularejection time T_(LVE) of a heart of a subject, comprising: a) at leasttwo electrodes, an alternating current (AC) source, and a voltmeter; b)an emitter and a sensor for electromagnetic radiation, both beingadapted to be attached to at least one of a fingertip and a toe of thesubject; and c) a processing apparatus comprising: i) one of the groupselected from an electrical bioimpedance analyzer and an electricalbioadmittance analyzer, ii) a pulse oximetry processor, and iii) aprocessing unit coupled to said analyzer and said processor.
 25. Asystem for determining the left-ventricular ejection time T_(LVE) of aheart of a subject, comprising: a) at least two electrodes, analternating current (AC) source, and an voltmeter; b) an ultrasoundemitter, and an ultrasound detector; and c) a processing apparatuscomprising: i) one of the group selected from an electrical bioimpedanceanalyzer and an electrical bioadmittance analyzer, ii) a Dopplervelocimeter for controlling said ultrasound emitter and for obtainingsignals from said ultrasound detector, and iii) a processing unitcoupled to said analyzer and said Doppler velocimeter.
 26. The systemaccording to claim 25, wherein said electrodes, said ultrasound emitterand said ultrasound detector are placed on a catheter.
 27. The systemaccording to claim 25 or 26, further comprising: d) an emitter and asensor for electromagnetic radiation, both being adapted to attach to atleast one of a fingertip and a toe of said subject, and wherein saidprocessing apparatus further comprises: iv) a pulse oximetry processor,said processing unit being coupled to said processor.
 28. A system fordetermining the left-ventricular ejection time T_(LVE) of a heart of asubject, comprising: a) at least two electrodes, an alternating current(AC) source, and an voltmeter; b) an emitter and a sensor forelectromagnetic radiation including infrared; c) a device applicable toa limb of said subject for obtaining data representing physical entitieswhich are changing during the stroke of said heart; and d) a processingapparatus comprising: i) one of the group selected from an electricalbioimpedance analyzer and an electrical bioadmittance analyzer, ii) apulse oximetry processor, iii) a processor for processing the dataobtained by said device, and iv) a processing unit coupled to saidanalyzers and said processors.
 29. The system according to claim 28,wherein said device is selected from the group comprising: an ultrasoundtransducer adapted to be attached to a wrist of said subject, a pressuresensor adapted to be attached to a wrist of said subject, and a pressuresensor adapted to be inserted in a peripheral artery of said subject.30. An apparatus adapted to be inserted into the esophagus of a subject,comprising: a catheter; at least two electrodes placed onto saidcatheter, and an ultrasound emitter and an ultrasound receiver placedonto said catheter.
 31. The catheter according to claim 30, wherein asingle transducer is used as said ultrasound emitter and receiver.